Risperidone, or 3-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-ethyl]-6,7,8,9-tetrahydro-2-methyl -4-H-pyrido[1,2-a]-pyrimidin-4-one, is a serotonin antagonist approved for the treatment of psychotic disorders such as schizophrenia. Its structure is shown in formula (1).
The compound and its pharmaceutical activity are identified in U.S. Pat. No. 4,804,663.
Various methods for making risperidone are known. Typically the synthesis includes forming the benzisoxazole ring moiety by cyclizing an oxime intermediate. For example, U.S. Pat. No. 4,804,663, which corresponds to EP 196132, discloses oximating a 4-(2,4-difluorobenzoyl)piperidine hydrochloride (2)
by treating with hydroxylamine to yield a corresponding oxime (3).
The oxime is cyclized by a base in water to yield 6-fluoro-3-(4-piperidinyl)-1,2-benzizoxazole, compound (4) in approximately 62% yield.
The benzisoxazole compound (4) is N-alkylated with the 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2a]pyrimidin-4-one hydrochloride, compound (5)
in the presence of sodium carbonate and potassium iodide in dimethylformamide, to yield risperidone base in a relatively low yield (46%). This last step was reportedly improved in WO 02/14286 and in WO 02/12200 by replacing the dimethylformamide with acetonitrile, isopropanol, methyl ethylketone or iso-butanol as the solvent.
An alternative oxime route is described in ES 2050069 wherein the starting piperidine compound (2) is first N-alkylated with the pyridopyrimidinone compound (5), under essentially the same alkylation conditions as above, to yield (63%) of a dihydrochloride of an alkylated ketone compound (6).
The ketone (6) is oximated by hydroxylamine hydrochloride to yield (76%) of an alkylated oxime (7).
The oxime (7) is then cyclized in the presence of a base in 80-85% yield to the desired risperidone base.
In addition to these prior art procedures, another oxime-based synthesis route has been proposed for compounds analogous to risperidone in EP 368 888 and in EP 453042. While not applied to risperidone, the general scheme suggests forming an oxime analogous to the compound of (7) by first converting a ketone (2) to the oxime (3). This oxime is then alkylated, prior to cyclization, by the corresponding pyridopyrimidine compound to yield an alkylated oxime analogous to compound (7). As in ES 2050069, the last step is to cyclize the oxime to form the benzisoxazole ring.
The use of a different oxime compound in forming risperidone is suggested in Spanish Patent No. 2,074,966. In this patent a pyran-containing oxime of the formula
is formed. After cyclization to form the isoxazole ring, the pyran ring is opened and ultimately reacted with an amino-pyridopyrimidinone compound to form risperidone. The patent also discloses the isolation of the “syn” isomer of the oxime molecule, using chromatographic methods, from the crude mixture having a “syn/anti” ratio of 3:1.
It would be desirable to provide another useful method and reagents for making risperidone, especially a method and reagents that can provide for improved results.